Research paper
Deep brain stimulation can suppress pathological synchronisation in parkinsonian patients A Eusebio,1,2 W Thevathasan,1,3 L Doyle Gaynor,1 A Pogosyan,1 E Bye,1 T Foltynie,1 L Zrinzo,1 K Ashkan,4 T Aziz,5 P Brown1,3 < Additional data are published
online only. To view these files please visit the journal online (http://jnnp.bmj.com). 1
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London, UK 2 Department of Neurology and Movement Disorders, Timone University Hospital, Marseille, France 3 Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK 4 Neurosurgery, King’s College Hospital, Denmark Hill, London, UK 5 Department of Neurological Surgery, John Radcliffe Hospital, Oxford, UK Correspondence to Professor P Brown, Department of Clinical Neurology, John Radcliffe Hospital, Oxford OX3 9DU, UK;
[email protected]
ABSTRACT Background Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective therapeutic intervention in severe Parkinson’s disease, its mechanism of action remains unclear. One possibility is that DBS suppresses local pathologically synchronised oscillatory activity. Methods To explore this, the authors recorded from DBS electrodes implanted in the STN of 16 patients with Parkinson’s disease during simultaneous stimulation (pulse width 60 ms; frequency 130 Hz) of the same target using a specially designed amplifier. The authors analysed data from 25 sides. Results The authors found that DBS progressively suppressed peaks in local field potential activity at frequencies between 11 and 30 Hz as voltage was increased beyond a stimulation threshold of 1.5 V. Median peak power had fallen to 54% of baseline values by a stimulation intensity of 3.0 V. Conclusion The findings suggest that DBS can suppress pathological 11e30 Hz activity in the vicinity of stimulation in patients with Parkinson’s disease. This suppression occurs at stimulation voltages that are clinically effective.
artefacts which are several orders of magnitude larger than the spontaneous fluctuations of the LFP.7 Thus, investigators have either recorded at projection sites of the STN, where stimulation artefact is less of a problem, or recorded the immediate after-effects of STN DBS in those patients with a delayed return of bradykinesia upon cessation of DBS. The findings have been mixed, with most studies reporting suppression of b activity,8e12 but one study failing to find such an effect.13 The authors of the latter study have since also recorded from the STN directly during DBS and again failed to show significant suppression of LFP power in the b band.14 Although this study was a technological feat, not all recordings had peaks in the b band prior to DBS so that power suppression may have been difficult to detect in these cases, a problem compounded by the recording of four patients on medication and four patients withdrawn from levodopa. Here, we use similar methodology to study the effects of STN DBS in a larger sample of 16 patients with evidence of pathological synchrony in the subthalamic region at baseline, prior to stimulation. Our aim was to address whether STN DBS suppresses local b activity when this is present.
INTRODUCTION
METHODS
Although pharmacological treatment in Parkinson’s disease is initially satisfactory, many patients suffer from severe fluctuations in their clinical state, involuntary movements and prolonged periods of bradykinesia and rigidity after a few years. These problems are difficult to manage and have led to a renaissance of invasive treatment strategies for late-stage Parkinson’s disease, particularly deep brain stimulation (DBS) of the subthalamic nucleus (STN). Many potential mechanisms of action of DBS in Parkinson’s disease have been suggested.1 One possibility, explored further here, is that DBS suppresses or over-rides pathologically synchronised oscillatory activity which acts as a noisy disruptive signal.2e5 One type of activity in particular has received attention in recordings from patients with Parkinson’s disease and involves exaggerated synchronisation at about 20 Hz, in the b frequency band. This is evident in the crosscorrelation of neuronal discharges, oscillations of the local field potential (LFP) and spike-triggered averages of LFP activity.3e6 The evidence that DBS may modulate b activity in patients with Parkinson’s disease is mixed and mostly indirect. The latter is because simultaneous recordings of STN LFPs during DBS were, until recently, obviated by stimulation-induced electrical
A complete description of the methods is available as supplementary material.
P Brown holds a consultancy with Medtronic Inc. Received 19 May 2010 Revised 27 August 2010 Accepted 2 September 2010 Published Online First 9 October 2010
This paper is freely available online under the BMJ Journals unlocked scheme, see http:// jnnp.bmj.com/site/about/ unlocked.xhtml
J Neurol Neurosurg Psychiatry 2011;82:569e573. doi:10.1136/jnnp.2010.217489
Patients and surgery Sixteen patients participated with informed written consent and the permission of the local ethics committees, and in compliance with national legislation and the Declaration of Helsinki. All had advanced idiopathic Parkinson’s disease. Implantation of bilateral STN DBS electrodes was performed sequentially in the same operative session under local anaesthesia, as previously described,15 in all but one patient (case 10; see table in supplementary material). The patients reported here are distinct from those reported by Kühn et al.10
Recordings Recordings were performed in the few days between electrode implantation and their connection to the pulse generator. The Medtronic electrodes used have four equally spaced contacts. Contact 0 was the lowermost and contact 3 was the uppermost (see supplementary material). Out of the 16 patients, recordings were possible on 28 sides (see table in supplementary material). We used a single-channel, isolated, high-gain (100 dB) amplifier7 with pass band (4e40 Hz) to record LFP 569
Research paper signals from the contacts of an electrode while another contact of the same electrode was stimulated. All patients were recorded while they sat in a comfortable chair after overnight withdrawal of their usual antiparkinsonian medication. Patients were instructed to rest quietly, and absence of voluntary movement was confirmed by continuous visual inspection. Initially, about 100 s was recorded from contacts 1/3 and 0/2 on each side with the patient at rest and with no stimulation. The spectral pattern was then analysed immediately off-line in Spike 2 using spectral averages and time-evolving spectral displays. Three of the 28 sides had no discrete spectral peaks, regardless of frequency (see table in supplementary material), and were not studied further. In the remaining 25 sides, we selected the contact pair with the highest peak power (contact pair 1/3 on 19 sides and contact pair 0/2 on six sides) for recording during subsequent stimulation. This was done to maximise our chances of detecting power suppression during DBS (ie, of avoiding a floor effect). The contact pair with the highest b activity has also been previously documented to be well positioned in STN and to concur with the site selected for chronic therapeutic stimulation.15e19 Thereafter, patients were recorded at the selected contact pair on a given side for a further 2 min without stimulation, the latter having been discontinued at least 20 min earlier. Then, unilateral DBS was begun at 1.0 V (19 sides), 1.5 V (five sides) or 2.0 V (one side), depending on time constraints and prior clinical information regarding efficacy. Stimulation was subsequently increased in step increments of 0.5 V (or 1.0 V on two sides) up to 3.5 V, or until side effects were encountered. Each new voltage was maintained for w100 s. When time allowed (12 sides in eight patients) at the end of the above slow ramping of stimulation, the latter was then discontinued for 100 s and thereafter stimulation re-presented for a further 100 s at a clinically effective voltage. This was performed so that we could determine whether any suppression of LFP activity during voltage ramping depended on a certain duration of stimulation or on a certain threshold intensity (see results). Monopolar simulation was delivered by a Medtronic external stimulator (type 3625) between active contacts 1 (when recording from 0/2) or 2 (when recording from 1/3) and a subclavicular surface electrode (pulse-width 60 ms; frequency 130 Hz). Clinical assessment, other than visual inspection, was not made until after all recordings were completed so as to avoid any influence on the LFP. Clinical assessments (items 20, 22 and 24 of UPDRS III) were not blinded. The lowest voltage (threshold) for clinically effective stimulation was determined separately on each side contralateral to the stimulation (see supplementary methods in supplementary material for further details).
Analysis Spectral analysis was performed in Spike2 v6, using serial FFT blocks of 256 data points (frequency resolution 0.78 Hz, Hanning window, windows not overlapped). These were visualised as time-averaged power spectra (figures 1, 2A) and time-frequency plots (figure 2B). Peaks were defined as local elevations of power in which the five contiguous bins centred on the peak had to be significantly different (p
